TY - JOUR
T1 - Suppression and regression of choroidal neovascularization by the multitargeted kinase inhibitor pazopanib
AU - Takahashi, Kyoichi
AU - Saishin, Yoshitsugu
AU - Saishin, Yumiko
AU - King, Andrew G.
AU - Levin, Robert
AU - Campochiaro, Peter A.
PY - 2009/4
Y1 - 2009/4
N2 - Objective: To investigate pazopanib hydrochloride, a multitargeted kinase inhibitor, for treatment of choroidal neovascularization (CNV). Methods: Choroidal neovascularization was induced in mice by rupture of Bruch membrane with laser photoco- agulation. Mice were treated with pazopanib by gavage or periocular injection, and the area of CNV was measured. Results: Twice-daily gavage of pazopanib, 100 mg/kg, suppressed the development of CNV by 93%. Treatment of established CNV between days 7 and 14 with 8, 40, or 200 mg/kg per day reduced CNV by 0%, 58%, and 71%, respectively. Substantial regression (40%) of CNV was also achieved after periocular injection of pazo- panib. A single oral dose of 4 or 100 mg/kg resulted in an area under the curve from time 0 to the last quanti-fiable concentration of 129.6 and 752.0 μg · h/mL, respectively. After 7 days of 4, 20, or 100 mg/kg twice a day by gavage, plasma levels were 1300, 4900, and 5800 ng/mL and levels in the retina/choroid were 4800, 28 800, and 38 000 ng/g of tissue. Conclusions: Orally administered pazopanib has good bioavailability to the retina/choroid and strongly suppresses CNV in mice. Treatment with pazopanib after CNV is established causes dose-dependent regression of CNV. Clinical Relevance: Pazopanib may be useful for treatment of CNV in humans.
AB - Objective: To investigate pazopanib hydrochloride, a multitargeted kinase inhibitor, for treatment of choroidal neovascularization (CNV). Methods: Choroidal neovascularization was induced in mice by rupture of Bruch membrane with laser photoco- agulation. Mice were treated with pazopanib by gavage or periocular injection, and the area of CNV was measured. Results: Twice-daily gavage of pazopanib, 100 mg/kg, suppressed the development of CNV by 93%. Treatment of established CNV between days 7 and 14 with 8, 40, or 200 mg/kg per day reduced CNV by 0%, 58%, and 71%, respectively. Substantial regression (40%) of CNV was also achieved after periocular injection of pazo- panib. A single oral dose of 4 or 100 mg/kg resulted in an area under the curve from time 0 to the last quanti-fiable concentration of 129.6 and 752.0 μg · h/mL, respectively. After 7 days of 4, 20, or 100 mg/kg twice a day by gavage, plasma levels were 1300, 4900, and 5800 ng/mL and levels in the retina/choroid were 4800, 28 800, and 38 000 ng/g of tissue. Conclusions: Orally administered pazopanib has good bioavailability to the retina/choroid and strongly suppresses CNV in mice. Treatment with pazopanib after CNV is established causes dose-dependent regression of CNV. Clinical Relevance: Pazopanib may be useful for treatment of CNV in humans.
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U2 - 10.1001/archophthalmol.2009.27
DO - 10.1001/archophthalmol.2009.27
M3 - Article
C2 - 19365030
AN - SCOPUS:65249175197
SN - 0003-9950
VL - 127
SP - 494
EP - 499
JO - Archives of ophthalmology
JF - Archives of ophthalmology
IS - 4
ER -